This communication reports the results of investigations on the effect of low molecular weight heparin (LMWH) on intraneuronal calcium release, and considers its possible relevance to the treatment of ischemic stroke. It previously was shown that intraneuronal injection of conventional heparin (MW 12,000) in vitro prevents glutamate-induced calcium release from intracellular stores through its blocking action on IP3 (inositol-1,4,5-triphosphate) receptors, and thus interferes with events occurring in the ischemic cascade. In the experiments reported herein, a LMWH of MW 4500 was shown to have these same effects when injected into a Purkinje cell in an in vitro cerebellar slice preparation, and also when administered externally (bath application). By contrast, conventional heparin works only when injected into the cell; bath application has no effect. The results are interpreted to mean that the larger conventional heparin molecule cannot pass through the cell membrane, while the smaller LMWH molecule does indeed enter the cell. In a clinical trial, LMWH begun within 48 hours of ischemic stroke onset in humans improved outcome at 6 months; conventional heparin given in a similar trial was without benefit. That one anticoagulant was beneficial while another failed suggests the possibility that the difference was independent of effect on the clotting system. The experimental data herein reported support the view that LMWH may benefit stroke victims by an action directly cytoprotective against the consequences of neuronal ischemia.